chr11-18279812-G-A

Variant names:

• chr11-18279812-G-A
• rs371535842
• NM_181507.2:c.*70C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181507.2(HPS5):​c.*70C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,440,388 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (19 hom.)
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.737
• Publications: 0 publications found

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

HPS5 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-18279812-G-A is Benign according to our data. Variant chr11-18279812-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 303864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000979 (149/152272) while in subpopulation SAS AF = 0.00477 (23/4822). AF 95% confidence interval is 0.00326. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.*70C>T		3_prime_UTR	Exon 23 of 23	NP_852608.1	Q9UPZ3-1
	HPS5	NM_001440902.1		c.*123C>T		3_prime_UTR	Exon 24 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.*123C>T		3_prime_UTR	Exon 24 of 24	NP_001427832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.*70C>T		3_prime_UTR	Exon 23 of 23	ENSP00000265967.5	Q9UPZ3-1
	HPS5	ENST00000396253.7	TSL:1	c.*70C>T		3_prime_UTR	Exon 22 of 22	ENSP00000379552.3	Q9UPZ3-2
	HPS5	ENST00000438420.6	TSL:1	c.*70C>T		3_prime_UTR	Exon 22 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00142 AC: 1834 AN: 1288116 Hom.: 19 Cov.: 18 AF XY: 0.00168 AC XY: 1093 AN XY: 649306

African (AFR) AF: 0.0000331 AC: 1 AN: 30180

American (AMR) AF: 0.000274 AC: 12 AN: 43766

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 615 AN: 24962

East Asian (EAS) AF: 0.000489 AC: 19 AN: 38842

South Asian (SAS) AF: 0.00788 AC: 646 AN: 81954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00605 AC: 33 AN: 5454

European-Non Finnish (NFE) AF: 0.000376 AC: 359 AN: 955312

Other (OTH) AF: 0.00273 AC: 149 AN: 54618

GnomAD4 genome AF: 0.000979 AC: 149 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74452

African (AFR) AF: 0.0000962 AC: 4 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.00104

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hermansky-Pudlak syndrome 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371535842; hg19: chr11-18301359; COSMIC: COSV100752240; COSMIC: COSV100752240;